chr12-49032761-G-C

Variant names:

• chr12-49032761-G-C
• rs1555188379
• NM_003482.4:c.11944C>G
• KMT2D p.Arg3982Gly

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-1 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -1 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4_Moderate

The NM_003482.4(KMT2D):c.11944C>G (p.Arg3982Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000704 (AC=1) in the gnomAD database across 1,420,778 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000654. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R3982Q: Benign/Likely_benign (ClinVar VariationId 1900574, 2 stars)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.28
• Publications: 0 publications found

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

KMT2D Gene-Disease associations (from GenCC):

• choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Illumina, PanelApp Australia
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, ClinGen
• branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000654 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KMT2D NM_003482.4	MANE Select	c.11944C>G p.Arg3982Gly	missense	Exon 40 of 55	Prot: NP_003473.3 UniProt:

KMT2D NM_003482.4

MANE Select

HGVSc / HGVSpc.11944C>Gp.Arg3982Gly

Exon rankExon 40 of 55

missense

Prot: NP_003473.3UniProt: O14686-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KMT2D ENST00000301067.12	TSL:5MANE Select	c.11944C>G p.Arg3982Gly	missense	Exon 40 of 55	Prot: ENSP00000301067.7 UniProt:
	KMT2D ENST00000683543.2		c.11944C>G p.Arg3982Gly	missense	Exon 40 of 56	Prot: ENSP00000506726.1 UniProt:
	KMT2D ENST00000685166.1		c.11953C>G p.Arg3985Gly	missense	Exon 39 of 54	Prot: ENSP00000509386.1 UniProt:

KMT2D ENST00000301067.12

TSL:5MANE Select

HGVSc / HGVSpc.11944C>Gp.Arg3982Gly

Exon rankExon 40 of 55

missense

Prot: ENSP00000301067.7UniProt: O14686-1

KMT2D ENST00000683543.2

HGVSc / HGVSpc.11944C>Gp.Arg3982Gly

Exon rankExon 40 of 56

missense

Prot: ENSP00000506726.1UniProt: A0A804HHR9

KMT2D ENST00000685166.1

HGVSc / HGVSpc.11953C>Gp.Arg3985Gly

Exon rankExon 39 of 54

missense

Prot: ENSP00000509386.1UniProt: O14686-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152146	Cov:33
GnomAD4 exome	AF: 7.04e-7	AC:1	Hom:0	AN:1420778	Cov:47
GnomAD4 genome Warning	AF: 0.00000657	AC:1	Hom:0	AN:152146	Cov:33
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	12948	0.0000431	1	23218

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.044	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.83	D
FuncVEP CTI	Benign	0.012
GPN-Star LLR	N/A	-6.1
GPN-Star score	N/A	6.1
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.93	T
Mutation Taster	N/A	81/19	polymorphism
MutationAssessor	Benign	0.0	N
PhyloP100	Benign	2.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.52	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Varity_R	N/A	0.26
VESM-3B	Benign	-3.3

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1555188379;

hg19: chr12-49426544;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar